Mechanistic insight into the dehydrogenation reaction catalyzed by an MLC catalyst with dual ancillary ligand sites

Abstract

Metal–ligand cooperative (MLC) catalysis is central to modern catalytic chemistry, notable for its ability to enhance efficiency. Traditional MLC catalysts with a single auxiliary ligand site have limitations in optimizing catalytic activity, prompting increased interest in employing dual active sites for improved performance. In this study, density functional theory (DFT) is employed to explore the catalytic mechanism of a ruthenium complex featuring a 2-(2-benzimidazolyl)pyridine ligand in the dehydrogenation of benzyl alcohol. This catalyst is distinguished by its ability to use both the O–H group of hydroxy pyridine and the N–H group of benzimidazole as auxiliary sites during the reaction. The research uncovers a dynamic switching mechanism of ligand active sites across different catalytic stages. Specifically, the catalyst utilizes the oxygen site of the pyridone ligand as the proton acceptor during the proton transfer stage, while the N–H group of the benzimidazole ligand serves as the active site during the critical hydride transfer stage. This site-switching mechanism is elucidated through molecular plane parameter (MPP) analysis and Extended Transition State – Natural Orbitals for Chemical Valence (ETS-NOCV) analysis, which reveal that the N-site-assisted pathway during hydrogen transfer is characterized by reduced ligand deformation and enhanced orbital interactions. These factors contribute to the observed mechanistic selectivity. This dynamic site-switching strategy effectively lowers the reaction energy barrier and improves catalytic efficiency. The insights gained from this study not only clarify the roles of the ligand in various catalytic stages but also offer valuable theoretical guidance for the development of novel MLC catalysts with dual active sites.

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Introduction

The rational design of catalysts to precisely control their activity, selectivity, and stability for the efficient and green conversion of specific chemical reactions is a shared objective among chemists. Metal–ligand cooperation (MLC),^1–3 as a core concept in modern catalytic chemistry, has garnered widespread attention and spurred intense research interest due to its unique catalytic mechanisms and outstanding performance enhancement potential.^4–6 The MLC strategy involves the ingenious incorporation of auxiliary ligands into catalysts, achieving synergistic interactions between the metal center and ligands.^7–11 This synergy not only enhances catalytic activity but also significantly improves reaction selectivity. Historically, milestone syntheses such as the Noyori–Ikariya^12–16 and Milstein catalysts^17–20 have successfully utilized the principles of MLC, pushing catalytic efficiency to new heights and bringing revolutionary advancements to fields like fine chemical synthesis, drug development, and energy conversion. However, despite these significant achievements, traditional MLC catalysts are often constrained by the design of a single auxiliary site, which limits the flexibility and scope of tuning catalytic activity. Consequently, exploring new MLC catalysts with multiple auxiliary sites^21–23 and high tunability to meet the demands of increasingly complex chemical reactions has become a forefront challenge and direction in current catalytic chemistry research.

In recent years, the synthesis of catalysts featuring dual ligand coordination sites has emerged as a pivotal trend within the realm of catalytic chemistry (Fig. 1a). In 2014, Milstein and colleagues achieved a milestone by synthesizing a Ru–PNNH pincer complex²⁴ endowed with dual auxiliary coordination sites. Despite the presence of these dual active sites, no site-switching process^25,26 was observed, thereby paving the way for the development of dual-site MLC catalysts. Subsequently, the Khusnutdinova group reported a novel ruthenium complex based on naphthyridinone, which they postulated to possess two potential deprotonation sites: an acidic CH₂ group linked to the phosphine arm and the NH moiety of the naphthyridinone.²⁷ This catalyst was employed in the dehydrogenation of primary alcohols. Although harboring two potential reactive sites, the Khusnutdinova team refrained from exploring the potential interplay between these active sites. Ayan Datta and Sreebrata Goswami et al. conducted a study that combines DFT calculations and experimental methods to reveal the ligand-mediated mechanism in the catalytic dehydrogenation of alcohols using a nickel clamp complex.²⁸ The research also highlights the significant role of quantum tunneling in the hydrogen transfer process, demonstrating its potential applications in alcohol oxidation and hydrogen storage.^29–33

Fig. 1 (a) MLC catalysts with dual active sites on the ligand; (b) the dehydrogenation reaction catalyzed by Ru MLC catalyst with dual-sites.

Fast forwarding to 2021, Beller et al. synthesized a ruthenium complex utilizing a phenylimidazoline ligand, which, upon preactivation, presented two potential active sites on the ligand.³⁴ Computational investigations suggested that interconversion between these two active sites was unlikely to occur.²⁶ In the same year, Suárez and colleagues crafted an iridium CNP pincer complex derived from phosphine ligands and N-heterocyclic carbenes.³⁵ Through a combined experimental and theoretical approach, they discovered that during hydrogen activation, the reaction was facilitated by the NHC moiety, whereas during carbonyl hydrogenation, the reaction was predominantly governed by the phosphine ligand side. Subsequently, an intramolecular proton transfer facilitated the switching between these two distinct active sites. In 2022, Suárez et al. successfully applied this dual-site cooperative catalyst to the more intricate reduction of nitrogen oxides, demonstrating the involvement of both ligand active sites in the reaction.³⁶ In 2023, Nanda D. Paul and colleagues synthesized a ruthenium catalyst, postulating that the two N-sites on the ligand played a significant role during catalysis.³⁷ Given this backdrop, it becomes evident that while these dual-active-site MLC catalysts exhibit promising catalytic activities, the presence of two reactive sites on the ligand often leads to intricate and elusive reaction mechanisms.

Recently, Kundu et al. synthesized and characterized a series of ruthenium complexes based on 2-(2-benzimidazolyl)pyridine ligands.³⁸ Notably, Cat. A′, incorporating 2-hydroxypyridine and benzimidazole moieties, demonstrated superior reactivity (Fig. 1b). This Cat. A′, with its dual ligand sites, piqued our research interest: Could there be a possibility of site-switching between these active ligand sites? Which auxiliary ligand site is favored during different stages of catalysis? To address these questions, we conducted density functional theory (DFT) calculations, aiming to elucidate the roles played by different ligand sites at various stages of the catalytic reaction. This theoretical endeavor holds the potential to offer valuable insights for the future design of novel MLC catalysts featuring two active sites.

Computational details

Density functional theory (DFT) calculations were carried out using Gaussian 16 software (version A.03).³⁹ Geometry optimization was performed at the M06-L⁴⁰/def2SVP⁴¹ level of theory. We evaluated a series of functionals (please refer to ESI, Table S1†) and ultimately selected the M06-L functional, striking a balance between computational cost and accuracy. Additionally, frequency analysis was conducted at the M06-L/def2SVP level to ensure the absence of imaginary frequencies in all intermediates and to confirm the presence of exactly one imaginary frequency in each transition state. Intrinsic reaction coordinate (IRC) calculations were executed for all transition states to validate the obtained results. To improve the accuracy of the calculated free energy values, single-point energies of the optimized structures were computed at the M06-L/def2-TZVP level, utilizing the SMD solvent model⁴² to mimic the reaction environment in 1,4-dioxane. These corrections were facilitated using GoodVibes software (version 2.0.3),⁴³ developed by Funes-Ardoiz and Paton. Furthermore, ETS-NOCV⁴⁴ and MPP analyses⁴⁵ were performed using Multiwfn software,⁴⁶ while the geometries of the crucial transition states were generated and visualized using VMD software⁴⁷ and CYLview software.⁴⁸

Results and discussion

The inner-sphere mechanism

The inner-sphere mechanism pathway, as illustrated in Fig. 2, starts from the more stable intermediate IM2 (please see the ESI, Fig. S8†).^49,50 For this pathway, the benzyl alcohol dehydrogenation reaction is primarily divided into two stages: H₂ formation and the regeneration of the metal hydride. In the H₂ formation stage, we considered two possible transition states: a four-membered ring transition state TS4_a (Ru–H⋯H⋯O–Ru) and a six-membered ring proton-shuttle transition state TS4_b ⁵¹ (Ru–H⋯H⋯O⋯H⋯O–Ru). Unlike the transfer hydrogenation mechanism, both TS4_a and TS4_b involve a two-electron transfer process, wherein a proton combines with the metal hydride to generate H₂. In TS4_a, the proton from benzyl alcohol directly combines with the metal hydride, resulting in H₂ formation and producing intermediate IM5. This transition state adopts a compact four-membered ring structure (Ru–H⋯H⋯O–Ru). In contrast, TS4_b involves a proton-shuttle mechanism, where the proton on the benzyl alcohol coordinated to the metal is transferred to the oxygen of another benzyl alcohol molecule. Simultaneously, a proton from this second benzyl alcohol combines with the metal hydride to generate H₂, leading to the formation of intermediate IM5. An IRC curve analysis further clarifies the proton-shuttle process occurring in TS4_b (please see the ESI, Fig. S4 and S5†). Computational results indicate that the proton-shuttle transition state TS4_b has an activation barrier of 23.4 kcal mol⁻¹, whereas the four-membered ring transition state TS4_a, due to ring strain, has a slightly higher barrier by approximately 1.0 kcal mol⁻¹. Subsequently, the H₂-coordinated intermediate IM5 releases H₂ in a slightly endothermic process (ΔG = 0.5 kcal mol⁻¹), generating the coordinatively unsaturated intermediate IM6, which provides an open site for the subsequent β-H elimination. The β-H elimination then proceeds viaTS5,²⁷ generating the metal hydride intermediate IM7. IM7 releases a molecule of benzaldehyde, forming IM1. Finally, a molecule of benzyl alcohol coordinates with IM1 to form intermediate IM2, thereby completing the catalytic cycle. The computational results suggest that, in the inner-sphere reaction pathway, the rate-determining step occurs in the H₂ formation stage, specifically at the proton-shuttle transition state TS4_b, with an activation free energy of 23.4 kcal mol⁻¹.

Fig. 2 Potential energy diagram for the inner-sphere dehydrogenation mechanism of benzyl alcohol.

The outer-sphere mechanism

As illustrated, the outer mechanism pathway starts from intermediate IM2 as the initiation point of the catalytic cycle. In the context of the outer mechanism, the catalytic cycle can be divided into two main stages: benzyl alcohol dehydrogenation and H₂ generation (Fig. 3). The benzyl alcohol dehydrogenation stage comprises two processes: proton transfer and β-H elimination. During the proton transfer process, the ligand carbonyl oxygen site primarily receives the proton. For the β-H elimination process, three possible scenarios were considered: (1) β-H elimination assisted by the ligand O site (TS8); (2) β-H elimination without assistance from any ligand site (TS2); and (3) β-H elimination assisted by the ligand N site (TS6). Firstly, in the reaction process assisted by the ligand O site, there are two possible pathways: a stepwise pathway and a concerted pathway. In the stepwise pathway, the substrate benzyl alcohol first transfers a proton and then undergoes β-H elimination. Intermediate IM2, via transition state TS7_a, transfers the proton from benzyl alcohol to the ligand carbonyl, forming intermediate IM8. Intermediate IM8, through transition state TS7_b (ΔG^‡ = 26.2 kcal mol⁻¹), releases a molecule of benzaldehyde, forming intermediate IM4. In the concerted pathway, intermediate IM2, via transition state TS8 (ΔG^‡ = 21.9 kcal mol⁻¹), directly releases benzaldehyde, forming intermediate IM4. The calculation results indicate that in the reaction process assisted by the ligand oxygen site, the concerted pathway is more favorable, with an activation free energy barrier of 21.9 kcal mol⁻¹.

Fig. 3 Potential energy diagram for the outer-sphere dehydrogenation mechanism of benzyl alcohol.

For the reaction pathways without ligand site assistance and with ligand N site assistance in β-H elimination, first, during the proton transfer from the alcohol in intermediate IM2 to the ligand carbonyl, the proton shuttle transition state TS1_b (ΔG^‡ = 6.0 kcal mol⁻¹) is lower in energy by 0.3 kcal mol⁻¹ compared to TS1_a (ΔG^‡ = 6.3 kcal mol⁻¹). Intermediate IM2, through the proton shuttle transition state TS1_b, forms intermediate IM9, which is an endothermic process (ΔG = 7.1 kcal mol⁻¹). Intermediate IM9, losing a molecule of benzyl alcohol, forms intermediate IM3. Subsequently, in the β-H elimination process from intermediate IM3 to form intermediate IM4, two possible transition states were considered: transition state TS6, formed by hydrogen bonding between a molecule of alcohol and the ligand N site, and transition state TS2, which does not involve any ligand site assistance. The calculation results indicate that the transition state TS6, with ligand N site assistance, has a lower energy barrier of 19.9 kcal mol⁻¹. In contrast, the transition state TS2, without ligand site assistance, has a significantly higher energy barrier of 49.8 kcal mol⁻¹.

During the H₂ generation stage, we also considered two possible transition states: intermediate transition state TS3_a and proton shuttle transition state TS3_b, with energy barriers of 20.7 kcal mol⁻¹ and 16.6 kcal mol⁻¹, respectively. Intermediate IM4, via the proton shuttle transition state TS3_b, releases H₂, forming intermediate IM1. Subsequently, a molecule of benzyl alcohol coordinates with intermediate IM1, regenerating intermediate IM2. The above calculation results indicate that in the outer mechanism pathway, the O site is first involved in the proton transfer process during the alcohol dehydrogenation reaction, while the subsequent β-H elimination switches to the N site. During the β-H elimination stage, the transition state TS6 with ligand N site assistance has a significantly lower energy than the transition state TS2 without ligand site assistance and is also lower than the transition states TS7_b and TS8 with ligand O site assistance.

Our calculations suggest that this catalyst follows a unique site-switching mechanism. In the proton transfer step of the acceptorless dehydrogenation reaction, the catalyst chooses the oxygen atom site of the pyridinone ligand. However, in the crucial hydride transfer step, the calculations show that the catalyst dynamically switches to the assistance of the N–H group of the benzimidazole ligand. In the final H₂ release step, the catalyst reacts again through the oxygen atom site of the hydroxy-pyridine.

To elucidate the phenomenon of site switching in the catalyst and the variations in transition state energy barriers, an ETS-NOCV was subsequently applied to TS6, TS7_b, and TS8. As shown in Fig. 4(a), the ETS-NOCV results indicate that the NOCV orbital energies for TS6, TS7_b, and TS8 are −53.90 kcal mol⁻¹, −22.39 kcal mol⁻¹, and −53.35 kcal mol⁻¹, respectively. Notably, TS7_b (ΔG^‡ = 26.2 kcal mol⁻¹) exhibits a relatively small contribution from its NOCV orbitals to the electron density changes. In contrast, TS6 (ΔG^‡ = 19.9 kcal mol⁻¹) and TS8 (ΔG^‡ = 21.9 kcal mol⁻¹) have larger absolute NOCV orbital energies with similar magnitudes, suggesting a significant contribution to electron density changes in these two transition states.

Fig. 4 (a) ETS-NOCV analysis; (b) molecular planarity parameter analysis.

To further explain the energy barrier differences between TS6 and TS8, a MPP analysis was performed.^52–55 In this analysis, the atoms in the transition state structures are colored based on their standard deviation of planarity (SDP) values, with darker colors indicating greater deviations from the fitted plane. Carbon atoms above the fitted plane are primarily colored red, while those below are blue. As shown in Fig. 4(b), TS6 has an MPP value of 0.079, indicating minimal deviation from planarity in its ligand. In contrast, TS8 has an MPP value of 0.179, with the sp² hybridized carbonyl carbon atoms appearing red, indicating significant deviation from planarity. This deviation favors the dynamic selection of the N-site on the benzimidazole ligand during the β-H elimination process.

Conclusions

This study utilizes density functional theory (DFT) calculations to elucidate the catalytic mechanism of a ruthenium complex with a 2-(2-benzimidazolyl)pyridine ligand in the benzyl alcohol dehydrogenation reaction. We present a detailed analysis of the dynamic switching mechanism of ligand active sites across various catalytic stages. Our findings indicate that the catalyst predominantly employs the oxygen site of the pyridone ligand during the proton transfer phase, while in the critical hydride transfer stage, it dynamically selects the N–H group of the benzimidazole ligand as the active site. This dynamic site selection mechanism substantially reduces the reaction barrier and enhances catalytic efficiency. These insights offer novel perspectives on the design of traditional MLC catalysts and highlight the capability of dual-site cooperative catalysts to optimize reaction pathways in complex processes. Our study not only advances the understanding of dual-site cooperative catalysis but also provides a robust theoretical foundation for the future development of highly efficient catalysts.

Author contributions

Gui-Xiang Zhou: calculation, data curation, writing – original draft. Cheng Hou: conceptualization, writing – review & editing, supervision, funding acquisition.

Data availability

Additional data are made available in supplementary tables in ESI† of this manuscript.

Conflicts of interest

The authors declared that they have no conflicts of interest to this work.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22163001).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo01767f

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